G-protein-coupled receptors constitute the largest family of cell surface receptor proteins. Upon activation, GPCRs couple to GTP-binding proteins that can be divided into four subclasses, Gαs-, Gαi/o-, Gαq and Gα12/13. Gs and Gi/o regulate adenylate cyclases leading to an increase (Gαs) or a decrease (Gαi/o) in cAMP production, or to an increase in intracellular calcium concentration (Gαq). Gα(12/13) activates Rho GEFs, which in turn activate Rho. GPCRs can also engage β-arrestins. Historically, β-arrestin-1 and β-arrestin-2 were believed to serve an exclusive role in GPCR desensitization. However, it has been shown that β-arrestins can also function to activate signaling cascades. Many human diseases are associated with the dysfunction of GPCRs. Thus, GPCRs represent some of the most attractive therapeutic or molecular targets in the pharmaceutical industry.
Insulin regulates the concentration of blood sugar and blood lipid levels through the promotion of glucose and lipid uptake into cells. Type 2 Diabetes Mellitus (T2DM or T2D) is a complex metabolic disorder characterized by hyperglycemia arising from a combination of insufficient insulin secretion together with the development of insulin resistance. T2D and obesity are closely linked, with obesity accounting for 80-85% of the risk of developing T2D. Incretin-based therapies represent a promising class of agents for the treatment of T2D. Incretins including the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP) are endogenous peptide hormones secreted from the intestine in response to food intake. GLP-1 and GIP exert their action through G-protein coupled receptor, the GLP-1 and the GIP receptors, respectively. GLP-1R is expressed in pancreatic β-cells as well as various tissues including liver, smooth muscle, heart, kidney, gastrointestinal tract, lungs, pituitary, white adipose tissues, and the central nervous system. GLP-1 lowers postprandial glucose excursion by potentiating glucose-stimulated insulin secretion from pancreatic β-cells and has recently been shown to promote β-cell survival in rodents. In addition, GLP-1 exerts extrapancreatic actions such as promoting gastric emptying, weight loss, intestinal growth and increasing insulin sensitivity in peripheral tissues.
A need exists in the art for better and more robust means for identifying agonists or activators displaying novel pharmacology of various GPCRs. There is also need in the art for new compounds and methods for treating diseases associated with insulin deficiency and high blood glucose. The instant invention addresses these and other currently unmet needs in the art.